TREATMENT REVIEW

Recurrent urinary tract infections (UTIs) are a major healthcare concern

for premenopausal, healthy, sexually active women. A practical approach tothe management and prevention of recurrent UTIs should be simple, practical,and cost effective. Low-dose or postcoital antimicrobial therapy can be effectivefor women with constellations of many recurrent UTIs, but for women with2 to 4 UTIs per year, the most cost-effective and empowering managementstrategy is patient-initiated antimicrobial treatment.[Rev Urol. 2005;7(1):11-17]

2005 MedReviews, LLC

R ecurrent urinary tract infections (UTIs) in premenopausal, sexually active women with anatomically normal urinary tracts are not perceived as a major clinical problem by the urology community. UTIs account for more than 7 million visits to physicians per year (1.2% of all office visits by women).1-3 The financial impact of UTIs, including recurrent and uncomplicated cases, is greater than 1 billion dollars in the United States alone.4 Over 80% of women who

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Recurrent UTIs in Premenopausal Women continued

had previous UTIs have recurrent and then later with some pessimism.14 clear up spontaneously changes sus-infections over the first 18 months of Sulfanilamide, introduced in 1937, ceptibility to recurrences. Mabeck6observation.5 Of these recurrent ushered in the era of modern antimi- found that 46.5% (20 of 43) ofinfections, three quarters are caused crobial therapy for UTIs.15 untreated patients had recurrentby reinfection with different organ- infections within 12 months, com-isms.6,7 Women with frequent reinfec- Has Modern Medicine pared with about 40% of antimicro-tions have a rate of 0.13 to 0.22 UTIs Created Recurrent UTIs? bial-treated patients. Similarly, Asscherper month (1.6 to 2.6 infections per In the 1800s, a woman suffering and colleagues17 found that reinfec-year).6,7 For premenopausal, healthy, from cystitis was bedridden for many tions occurred in 34% of patients withand active females, recurrent UTIs are weeks while the physician attempted asymptomatic bacteriuria treated witha major healthcare concern. to assist Mother Nature in achieving antibiotics, compared with 29% a cure. The patient usually recovered receiving a placebo during a 3- toHistorical Management of if she did not develop pyelonephritis 5-year follow-up. It is possible thatUTIs in Women or more complicated UTI. Felix autoimmunity can result from onlyIn the 1800s, management of bladder Guyon (18311920)16 observed that symptomatic bacteriuria. These areinflammation included conservative many patients with cystitis did not interesting observations, but, unfor-initial treatments (bedrest, warm experience recurrences after recovery. tunately, the modern woman doesherbal compresses, baths, opiate- He proposed that this acquired not want to suffer 4 weeks of cystitic symptoms while waiting for her immune system to heal the infection.Recurrent UTIs are a significant problem for many women, despite ourbroad array of very successful antimicrobial agents. Evaluation of Women with Recurrent UTIs Urinalysisbased enemas) whereas more aggres- immunity was a result of autovacci- Microscopy is a valuable adjunctivesive therapy was reserved for nation from absorption of toxins or diagnostic tool for patients with uri-patients who did not improve or from bacteria in a state of modified nary symptoms, and, if available,deteriorated during initial therapy. virulence. This is an interesting should be considered for patientsAggressive treatment included observation, considering that recur- presenting with cystitis. There aremustard- or ammonia-based plasters, rence is currently a significant problem limitations in detecting microscopicoral alkali, bleeding (cupping, leeches, for many women, despite our broad bacteriuria and pyuria because ofor direct bleeding) and large doses of array of very successful antimicrobial lack of standardization for theacid solutions.8 In the later 1800s, agents. Is it possible that with our microscope itself (including magnifi-William Osler9 described an initial modern medical practice of initiating cation) and the volume of urine thattreatment consisting of absolute rest, early antimicrobial therapy for symp- can be observed, as well as if thecold applied to the loins or dry cupsto the lumbar region, and amylnitriteand quinine in large doses. If these Urine culture is the gold standard for the diagnosis of UTI, althoughtreatments were ineffective, therapy urine must be collected properly and cultured quickly or refrigerated.involved acetates of lead and opium,followed by ergot, gallic and tannicacid, or diluted sulphuric acid. The tomatic cystitis we have created the urine is spun or unspun, stained orera of modern evidence-based urolo- scenario of recurrent UTIs in pre- unstained. However, if microscopy isgy began with the recognition that menopausal women? When Mabeck6 performed, the absence of pyuriacystitis (suppuration of the bladder) followed 23 untreated nonpregnant should cause a physician to recon-was infectious in origin. Beginning women with acute symptomatic cys- sider UTI as a diagnosis. Indirect dip-in the 1900s, trials with chemothera- titis, 21 lost their symptoms after stick test for bacteriuria (nitrite) orpeutic agents such as hexamine, 4 weeks (even though the bacteriuria pyuria (leukocyte esterase) can bephenazopyridine, hexylresorcinol, did not disappear as quickly). helpful. Although they are less sensi-and Mercurochrome10-13 were under- However, these studies did not neces- tive than microscopic examinationtaken, initially with some success sarily suggest that allowing a UTI to of the urine, they provide additional

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confirmation of a UTI when contem- probably not necessary to repeat a always be the most appropriateplating empiric therapy and while urine culture at each episode. Urine screening procedures.culture results are pending. culture would be mandatory, however, if the patient does not respond to Traditional Management ofUrine Culture empiric therapy. Recurrent UTIsUrine culture is a standard criterion for Traditionally, it was taught that sig-the diagnosis of UTI, although prob- Other Investigations nificant bacteriuria had to be con-lems exist for this gold standard. Many patients with recurrent UTIs firmed by culture before antibioticsUrine must be collected properly (mid- are referred for urologic opinion and were prescribed. Employing this tra-stream or catheterized specimen) and subsequently undergo both radio- ditional approach, each UTI episodecultured quickly or refrigerated. logic investigations and cystoscopy. in young women was associated onTraditionally, significant bacteriuria Radiologic studies are unnecessary average with 6.1 days of symptoms,is noted when the bacterial colony- for the evaluation of the healthy, sex- 2.4 days of restricted activity, 1.2 daysforming unit counts reach 105/mL. ually active, premenopausal woman.18 of not attending work or school, andThe problem with this somewhat Similarly, cystoscopy rarely will detect 0.4 days of bedrest.19 Although many teachers adhere to this traditional approach (perhaps based on aRenal ultrasonography is the preferred urinary tract screening misguided evidence-based criterion,imaging technique because it is noninvasive, easy to perform, and rela- FDA guidelines, or interpretation oftively inexpensive. costbenefit ratios), most physicians will treat an uncomplicated UTI with antibiotics, based on a description ofartificial cutoff is that many women significant pathology that would the patients symptoms, particularlywith symptomatic UTIs present with change the outcome of therapy.18 if confirmed by urinalysis (eithermuch lower bacterial counts (such However, further investigations are microscopy or nitrite/leukocyteas 102/mL), whereas patients with important if a patient is believed to esterase dipstick) (Figure 1).asymptomatic bacteriuria can have have any of the following: hema- First-line therapy for acute uncom-much higher counts. turia, a complicated UTI suggested plicated cystitis in women includes by a history of calculi, obstruction nitrofurantoin (the macrocrystallineShould Cultures Be Performed at (upper or lower urinary tract), neuro- preparation is better tolerated),All in Women With Recurrent UTIs? pathic bladder, recent genitourinary trimethoprim-sulphamethoxasoleBecause there are many inherent surgery or catheterization, unusual (TMP-SMX), trimethoprim (TMP)limitations and inaccuracies in urine organisms (such as tuberculosis, fun- alone, or a fluoroquinolone (particu-collection and culture results, one has gus, or urea-splitting organisms), larly in areas where TMP-SMX resist-to carefully evaluate the rationale for compromised immune system, dia- ance rates approach 20%). Three daysobtaining a urine culture in all patients betes, or renal failure. Similarly, of therapy appears to be optimalpresenting with simple uncomplicated investigations are required in patients because it results in similar cure ratescystitis. As will be noted later in this who do not respond to appropriate but with decreased costs and fewerarticle, a clinical diagnosis of UTI antimicrobial therapy after 5 to 6 days side effects compared with 710 daysis based on symptoms, and empiric of treatment. The excretory urogram of therapy, and lower recurrencetherapy with modern antibiotics is has been the traditional routine exam- rates compared with single-doseextremely successful. It can be argued ination method of evaluating patients therapy (reviewed by Schaeffer.)20that it would be cost effective in with complicated UTI and although itpatients with recurrent UTIs to first remains useful, it is not the ideal Prevention of Recurrent UTIsestablish the presence of significant screening test today. Currently, renal Conservative Approach to Preventionbacteriuria associated with an episode ultrasonography is the preferred uri- A number of risk factors, other thanof symptomatic cystitis, and then nary tract imaging technique because sexual activity, have been identifieddocument that both symptoms and it is noninvasive, easy to perform, in patients with recurrent UTIs.bacteriuria resolve with antimicro- and relatively inexpensive. CT and Contraceptive methods employing abial therapy. Once this has been con- MRI offer the best anatomical detail, diaphragm and/or spermicides (includ-firmed in a specific patient, it is but because of cost they may not ing spermicide-covered condoms) and

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Figure 1. A proposed practices (see Table 1) has proven to

treatment algorithm for First UTI episode premenopausal women be effective in reducing the incidence presenting with recur- of recurrent UTIs. rent urinary tract infec- tion (UTI). Antimicrobial Prophylaxis Physician diagnosis Culture The 2 contemporary strategies employing a prophylactic antibiotic regime to prevent recurrent UTIs include long-term low-dose prophy- Empiric antimicrobial therapy lactic antimicrobial treatment or post- coital antibiotic treatment. However, it does not appear that these strategies Recurrence of UTI alter the long-term risk of recurrence. Patients with frequent UTIs who take prophylactic antimicrobial agents for Lifestyle changes1 extended periods (for example, as Cranberry juice/extract long as 6 months) decrease their infections during prophylaxis, but the rate of infection returns to pre- Recurrent UTI treatment rates when prophylaxis is stopped.26,27 Long-term antibiotics do not appear to alter the patients basic susceptibility to infections.20 4 UTI/year 4 UTI/year Antimicrobial agents used for long- term low-dose prophylaxis include TMP-SMX (or TMP alone), nitrofuran- Constellations Episodic toin, cephalexin, and the fluoro- of UTIs UTIs quinolones. The dose is usually about a quarter the usual daily dose. Nitro- furantoin (because of rapid absorption Low-dose Postcoital Patient-initiated in the upper intestinal tract) produces antimicrobial antimicrobial antimicrobial minimal fecal resistance and less prophylaxis2 prophylaxis3 therapy4 vaginitis. It is, however, associated with more adverse reactions (eg, acute 1. Lifestyle changes: discontinue spermicides, feminine hygiene products, practice proper toileting habits pulmonary reactions, allergic reac- 2. Culture for breakthrough UTI; change antibiotic 3. Patient-initiated therapy for breakthrough UTI tions, liver problems). Most of these 4. Culture if no response by 48 hours; change antibiotic long-term adverse reactions occur in older patients. TMP-SMX is a power- ful prophylactic agent in preventingtampon use have been associated with tobacilli has been suggested but not reinfections in the female by clearingincreased risk of UTI.21,22 Contraceptive proven.24 It is probable that in the E. coli from the rectal and vaginalmethods should be changed, spermi- future, some form of immunization flora, but can be poorly tolerated withcidal agents should be discontinued, program will be the key to preven- potentially life-threatening sideand patients should consider using tion of recurrent UTIs.25 It is probably effects and the development of TMP-pads instead of tampons. Drinking appropriate to suggest that patients SMX resistant strains within the gutcranberry juice or cranberry extract stay hydrated, void regularly, avoid flora. Fluoroquinolones are probablyappears to be a safe and possibly feminine hygiene products such as the most effective agent for UTI pro-effective method of reducing the fre- vaginal douches and scented bubble phylaxis but should probably bequency of recurrent UTIs in some baths, and practice proper toilet restricted to women with acute symp-women.23 Attempting to change the habits (including early postcoital tomatic cystitis in which there is sig-vaginal flora by douching with lac- voiding), although none of these nificant antimicrobial resistance or to

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patients with intolerance to TMP-

SMX, TMP, or nitrofurantoin. Nicolle Table 1and Ronald28 summarized the effec- Prevention Strategies for Women withtiveness of prophylactic therapy in the Recurrent Urinary Tract Infectionmanagement of women with recurrentUTIs and noted that recurrences dur- Conservative lifestyle changes (see text)ing prophylaxis are decreased by 95%. Cranberry juice/extract prophylactic therapy Acute cystitis is more common in Physician-directed episodic antimicrobial therapysexually active women and a number Low-dose prophylactic antimicrobial therapyof studies have shown that postinter-course therapy with antimicrobials Postcoital prophylactic antimicrobial therapysuch as nitrofurantoin, cephalexin, Patient-initiated antimicrobial therapyand TMP-SMX taken as a single doseeffectively reduces the incidence ofreinfection.29,30 The rationale behind effectiveness and cost of patient-ini- believed that fluoroquinolones arepostintercourse therapy27 is based on tiated single-dose antibiotic therapy the ideal medication for self-startthe fact that intercourse results in the to antibiotic prophylaxis for women therapy because of their broad spec-introduction of bacteria from the with frequent UTIs. Thirty-eight trum of activity compared to otherurethra into the bladder. In the absence women were randomized to either potential alternatives (nitrofurantoinof voiding, the bacteria grow after continuous low-dose TMP-SMX or and TMP-SMX). The culture shouldovernight incubation to the point intermittent self-administration of a be brought to the office as soon aswhere voiding and other host defense single postcoital dose of TMP-SMX. possible and if the culture is positivemechanisms do not eradicate them. The infection rate in the prophylaxis and the patient asymptomatic, thenAn antibiotic taken immediately after group was 0.2 UTI/patient-year versus another culture should be performedintercourse presumably kills or arrests 2.2 UTI/patient-year in the self-treat- 7 to10 days after therapy to determinethe growth of sensitive bacteria ment group. This study was also efficacy. If the patient has symptomsbefore they reach the critical concen- important in confirming that a UTI that do not respond initially to antimi-tration required to establish an infec- can be diagnosed by patients. In fact, crobial therapy, additional culture and susceptibility tests of the initial culture specimens are performedAn antibiotic taken immediately after intercourse presumbably kills or and therapy adjusted accordingly.arrests the growth of sensitive bacteria before they establish an infection. Although this approach is scientifi- cally and clinically sound, it may not be time- and cost-effective, andtion in a susceptible individual. This 35 of the 38 UTIs diagnosed by patients would be required to submitapproach appears to be efficacious, patients were confirmed by culture. a minimum of 2 urine cultures. Withcost effective, and well tolerated by Thirty of the 35 UTIs responded clin- success rates in excess of 95% withpatients. In a placebo-controlled ically and microbiologically to treat- fluoroquinolone therapy, one mighttrial,30 the infection rate observed ment. No complications occurred in question the usefulness of cultures inwith postcoital TMP-SMX was 0.3 any of the 5 failures. women with recurrent UTIs, except,per patient-year compared with It has been suggested that a more of course, in the case of patients who3.6 per patient-year in placebo-treated accurate approach to self-diagnosis do not respond clinically to empiricwomen. Depending on frequency of and self-start therapy would be to antibiotic therapy.intercourse, postcoital prophylaxis give patients a dip slide device to Gupta and colleagues33 allowedusually results in less antibiotic culture the urine and instruct them women to diagnose their UTIs anduse than does continuous low-dose to perform a urine culture when immediately initiate treatment withantimicrobial prophylaxis. symptoms of UTI occur.32 The patient 3 days of fluoroquinolone antibiotics. would then self-start a 3-day course To analyze the accuracy of self-diag-Patient-Directed Self-Treatment of empiric full-dose antimicrobial nosis in the study, a midstream spec-of Recurrent UTIs therapy immediately after performing imen of urine (MSSU) was submittedWong and colleagues31 compared the the culture. The same investigators32 to the laboratory for culture. Repeat

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Recurrent UTIs in Premenopausal Women continued

urine cultures were submitted 10 and a frustrating constellation of very management plan saves valuable30 days after treatment as part of the frequent UTIs (and it is recognized time (for both the physician andexperimental protocol. The investi- that UTIs tend to cluster in some patient), reduces expense (eg, unnec-gators also interviewed the patients women). Although it does not change essary cultures, office visits, time offposttherapy. One hundred and sev- the long-term prognosis of future work), and allows for an early initia-enty-two women (average age UTIs, it certainly allows the patient tion of therapy with no apparent23 years), predominantly white, un- the chance of a long period without increase in treated episodes.married, and sexually active, had cystitis-like symptoms. For sexuallyat least 2 UTIs the previous year. active women with frequent UTIs, ReferencesEighty-eight of these 172 women postcoital antibiotic therapy appears 1. Patton JP, Nash DB, Abrutyn E. Urinary tract infections: economic considerations. Med Clinself-diagnosed 172 UTIs. A uropatho- to successfully reduce the frequency North Am. 1991;75:495-513.gen was cultured in 84%, sterile pyuria of symptomatic recurrent episodes 2. Hooton TM, Stamm WE. Diagnosis and treat- ment of uncomplicated urinary tract infection.was identified in 11%, and in only 5% of cystitis. For motivated and active Infect Dis Clin North Am. 1997;11:551-581.was pyuria or bacteriuria not detected. women who suffer 2 to 4 UTIs per year, 3. Schappert SM. Ambulatory care visits to physi-Clinical cures (complete eradication a patient-initiated treatment strategy cian offices, hospital outpatient departments, and emergency departments: United States, 1996.of symptoms) were noted in 92%, for their recurrent UTIs should be Vital Health Stat. 1999;13:I-IV, 1-39.microbiological cures (eradication of considered. It is appropriate to make 4. Rosenberg M. Pharmacoeconomics of treatingbacteria) were noted in 96%. There sure that at least 1 symptomatic uncomplicated urinary tract infections. Int J Antimicrob Agents. 1999;11:247-251, discussionwere no adverse events and almost episode of cystitis is associated with 261-264.100% of the patients were very happy a positive culture and that patients 5. Harrison WO, Holmes KK, Belding ME, et al. Awith this management plan. symptomatically resolve on a 3-day prospective evaluation of recurrent urinary tract infections in women. Clinical Research course of antibiotics. Once this is 1974;22:125A.A Practical Plan for Women established, there is evidence that 6. Mabeck CE. Treatment of uncomplicated uri- nary tract infection in non-pregnant women.With Recurrent UTIs women with recurrent UTIs can Postgraduate Med J. 1972;48:69-75.For premenopausal women with accurately self-diagnose and self- 7. Guttmann D. Follow-up of urinary tract infec-recurrent UTIs, particularly sexually treat uncomplicated cystitis (as accu- tion in domiciliary patients. In: Brumfitt W, Asscher AW, eds. Urinary Tract Infection,active women, it may not be appro- rately as any physician). This becomes Proceedings. London: Oxford University Press;priate to continue with the status a very self-empowering treatment 1973:62-73. 8. Todd R. Clinical Lectures on Certain Diseases ofquo and dogmatic approach of strategy for many women. Physicians, the Urinary Organs and Dropsies. Philadelphia:physician-directed investigations, cul- however, are not superfluous. A Blanchard and Lea; 1857:230-261.ture, and antibiotic prescription for patient-initiated treatment of recur- 9. Osler W. Diseases of the kidneys. In: Principles and Practice of Medicine, 4th ed. New York:each episode. Antibiotic prophylaxis rent UTI still remains a physician- Appleton; 1892:849-863.is effective for women who develop directed management strategy. This 10. Davis E, White E. Urinary antisepsis: further

Main Points Recurrent urinary tract infections (UTIs) in healthy premenopausal women are a major health concern, and UTIs account for 7 million physician visits per year at a cost of 1 billion dollars. Treatment of UTI in women has evolved from historically very conservative treatments, such as bedrest and herbal compresses, to current modern practices, which include use of antibiotics such as nitrofurantoin, trimethoprim-sulphamethoxosole (TMP-SMX), trimethoprim (TMP), and the oral fluoroquinolones. Risk factors for recurrent UTIs include use of a diaphragm and/or spermicides, and tampon use. Certain lifestyle changes are suggested to help reduce incidence of UTIs, but they have not been proven to be effective. Two other contemporary strategies employed in preventing recurrent UTIs are long-term low-dose prophylactic antimicrobial treatment and postcoital antibiotic treatment. These treatments have proven effective over extended periods of use (more than 6 months), but patients return to pretreatment rates of infection after prophylaxis is stopped. Studies have shown that patients can effectively diagnose their own UTIs and self-initiate treatments with the same success rate as physicians. This is a self-empowering strategy for many women and also helps save time and money. Physicians should still play an important management role.